Clarithromycin (structural formula I), also known as methyl-erythromycin, is a macrolide antibiotic obtained from methylation of 6-position hydroxyl group of erythromycin. It exhibits excellent anti-bacterial activity against Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, mycoplasma and chlamydia. Its activity is 2-4 times stronger than erythromycin. However, its toxicity is only about half (½) to one twentyfourth ( 1/24) of the toxicity of erythromycin.

U.S. Pat. No. 4,331,803 discloses a method of making clarithromycin by protecting the hydroxyl group at 2′-position and the dimethylamine group at 3′-position of erythromycin A, conducting methylation of 6-position hydroxyl group of erythromycin A, and removing the protective groups from erythromycin. Because the hydroxyl group at the 11, 12, and 4′ positions of erythromycin A can be easily methylated in a methylation reaction, many by-products are produced. It makes purification of the product difficult and affects the quality and the yield of the product.
In order to effectively methylate hydroxyl groups at the 6-positions, EP0272110 discloses a method of preparing clarithromycin. First, erythromycin A 9-oxime is etherified with an acid catalysis to protect the hydroxyl group at the 9-position. Next, the hydroxyl groups at the 2′-position and 4″-position are silylanized to be protected. Then, the hydroxymethylation reaction is conducted at the 6-positions. Finally, hydrolyzation is conducted to remove the protecting groups at the 2′-position, the 4″-position and the 9-position to obtain clarithromycin. This technological route is long and the yield is not high. Morever, because macrolide antibiotic is not stable to acid, when an acid catalysis is used to protect the hydroxyl group at the 9-position, erythromycin A 9-oxime is easily destroyed, thereby the yield is reduced. The total yield is about 50% (according to erythromycin A 9-oxime).